First of its kind study pits psilocybin against a common antidepressant | Hacker News Reader

First of its kind study pits psilocybin against a common antidepressant

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65 pointsgmays46 comments

Related prior discussion: https://news.ycombinator.com/item?id=26816444

25 is a pretty fat dose. Seems excessive for a scientific study...

I always wonder how these people running the studies choose their doses. Do we want the participants to have a smooth/pleasant trip? Or have an white knuckle, ego-obliterating flight through space?

This reminds me of another study I read where participants were given 100+mg doses of liquid ketamine straight to the dome. The participants frequently k-holed.

Maybe the science says otherwise, but personal experience tells me you don't need to melt your fucking face to experience the anti-depressant effects of psychedelics. It can be destabilizing to some.

It would be really interesting to study the dose response curve in regard to a single thing like depression. Do microdoses or mild doses help more or less than a Zoom call with God dose?

For a medical use I'd be concerned about the unpredictability of the experience with high doses. A traumatic or chaotic trip could make depression worse or possibly trigger other latent psychological issues.

I imagine it would get really expensive real fast to test the whole range of, what, at least a few dozen substances? Are there any efforts to make running experiments cheaper and faster?

25 is as they say 'medium-to-heavy dose'. It's not as excessively high as you make it sound and it isn't quite 'an white knuckle, ego-obliterating flight through space'

It's definitely a 'proper trip' but you are making it seem like a DMT breakthrough amount.

Yeah, agreed. I know mushrooms are highly variable in their psilocybin and psilocin content, but it’s generally around 1% of dried mass for cubensis from what I’ve read. So in this case that’s what, 2.5 grams of mushrooms about? That’s not nothing, but it certainly isn’t an ego death sort of dose. I know a lot of people that will take 3.5 grams for a typical “journey” when they’re seeking to get in there and do some internal work.

It seems like a perfectly fine dose for a study like this: not too overwhelming and not too small.

I guess we can agree to disagree. You can absolutely experience ego death in this range (or at least 'ego-shaking'). An 1/8th is pretty normal yeah for the typical recreational user, but I don't think that's a great benchmark for a science experiment. Lots of people have scary unpleasant experiences with an 1/8 or less.

Pharmaceutical grade psilocybin is gonna be a lot more potent than average street mushrooms.

Everyone has different bodies and react differently to drugs. I can assure you that 25mg is a heavy dose especially for those who are not experienced with psychedelics. My whole point is that some of these tests are being administered by scientists who have no experience with the drug, and maybe they should be more careful.

I would use different language to describe a DMT trip, but the imagery wasn't supposed to be the main focus of my comment. Just for an additional reference check out this old study and its take on dosage:

https://erowid.org/references/texts/show/5665docid5442

administered 20-70mg but eventually settled on "30 mg. as a standard, moderate dose". But'moderate' may mean many things. Leary, later in the same paper, says "Psilocybin produces temporary states of spiritual conversion, interpersonal closeness and psychological insight. Forty-five percent of the entire inmate group clearly underwent a mystical, transcendent, death-rebirth experience."

There's some research suggesting that the highest dose you can hit without inducing undue anxiety will be the most effective. As one might expect, this is similar to a tolerable recreational dose that most people would give themselves.

https://link.springer.com/article/10.1007/s00213-011-2358-5

You might expect 35mg psilocybin from 1/8 oz of mushrooms, which is a pretty mid to high, all day trip dose. So 25mg is strong but definitely not "ego death" strong.

Psilocybin content varies wildly in street mushrooms. I don't think a comparison between pharmaceutical grade psilocybin and illicit uncontrolled mushrooms is very useful.

I've witnessed lots of people losing their shit after eating an eighth.

It's still the same substance. The main difference is that with street mushrooms there's risk the dosage will be much higher, and that risk isn't there with a properly measured dose in a study.

Yep same substance but you misunderstand my point.

The risk here is that street mushrooms usually are going to be LESS potent than people think. What happens now, is that people pull the random statistic out of thin air saying "well 3.5g is about 35mg psilocybin so 25mg is good for the study." In reality, this dosage might end up being much higher than many of the positive anecdotes about "eating an eighth". And again, there's a million horror stories that use that same 3.5g weight.

That's why its silly to compare pharma-grade psilocybin with anecdotal evidence of street mushroom potency.

> Do we want the participants to have a smooth/pleasant trip? Or have an white knuckle, ego-obliterating flight through space?

A bit ignorant here. Isn’t this 25mg?

Or, is this a more concentrated dose than say normal shrooms where anywhere from 0.5-1-2g to even 5g would take you to the moon?

Seems reasonable to be honest.

The relationship between psilocybin and mushrooms is like the one between caffeine and coffee.

I totally agree with you, but on the other hand, am also interested in the related study question of: "What happens if we just melt some randos fucking faces off with shrooms?"

Will be interesting to read the paper

Hmm.. I'd argue you need that 'melt-your-fucking-face' experience to truly experience breakthrough. But then again, people react differently to everything

> While members of the psychedelic cohort received 25 milligrams of psilocybin during the sessions, considered a medium-to-heavy dose of the drug, those in the antidepressant group received 1 milligram. Such a low dose is typically provided in psychedelic studies in lieu of a placebo

Doesn't seem like well-designed study.

Can you explain why for those of us unfamiliar?

Well it's not actually a placebo to start with.

There is no way to placebo control a psychedelic really, as that effect is easily discerned, even in a closed label trial. Therefore, a comparison protocol is used instead, which is anyway superior to pure placebo control.

A different psychedelic, which is not expected to have an antidepressant effect, or a low, psychoactive but not antidepressant dose. Or known non-psychedelic antidepressants which have been placebo tested.

I think the concern is that you could still be getting pharmacodynamic effects at 1mg, so the control wouldn’t really be a control.

It’s entirely feasible that you could get good results and limited side effects at dose x, and poor results overwhelmed by side effects at dose 25x.

I agree that this is a bad flaw but the reasoning about the “nocebo” effect does make sense: administering a placebo actually confounds the results if the participants know it’s a placebo, and it will be pretty obvious it the pill you took doesn’t have any psychedelics.

Studies like these are inherently difficult, this isn’t an issue of poor design.

The article specifically says this is to prevent nocebo effects.

You criticize the study but don't provide any arguments against the methodology. Tell us what you know about WHY they give people low doses in the control group, then explain why you think a different method would be better. These aren't idiots designing studies.

Not the parent but perhaps allowing for a third group with no antidepression medication.

How would one make that work though in this case?

TFA features a very reasonable explanation in the next few sentences. If participants are going to a session where they'll be essentially locked in with a psychiatrist for a few hours and take only a placebo, they'll know it, and they'll get more depressed from knowing that they're in the placebo arm. So instead a small dose is provided which has some lesser effects, avoiding to break the participants' "blindness" to the protocol.

Well, true, but it seems hard to design such a study comparing psychedelics and common antidepressants.

Because a antidepressant works pretty much on its own. But when you treat with psychedelics, you have to have a very professional therapist guiding the patient, otherwise you will get all kinds of effects. (So I argue success depends very much on the therapist)

And a patient will notice, whether they just get a mushroom trip, or not. So what they did, they gave the control group 1 mg of antidepressant and told them, they are microdosing psilocybin.

Not really ideal, but how to improve?

It's a valid comparison design. An alternative is to use a high dose of a known non-antidepressant psychedelic, if one exists, as control. That would have to be something outside ergoloid, tryptamine and psylocybin families, which are likely to have those effects.

Tough problem.

Aren't psychedelics by definition mind altering? Sounds hard to find a psychedelic that isn't influencing the mind.

Some mild hallucinogenics might work, but then the participants may not have mushrooms experience before, otherwise they know when to be fooled.

> “In hindsight I wish we’d made these other measures of well-being the primary outcome measure,” he said. “However the world — the Food and Drug Administration, the European Medicines Agency — doesn’t recognize those measures as valid.”

Am I understanding this correctly? Other academics are critical of the outcome measured, but it was specifically chosen because of recognition by national authorities.

If I understood it correctly I took it to mean that the organizers of the study would have preferred to lean primarily on what government health agencies see as secondary or invalid measures of well-being.

Wasn't this tested 50 years ago and then sort of left dormant?

Psychedelic psychotherapy was left as a casualty to the war on drugs.

? The war on drugs didn't prevent a massive rise in opioid medication

Are opioids psychoactive?

Yes, but not hallucinogenic or psychedelic. (Whichever word you prefer.)

> Are opioids psychoactive?

Yes, obviously.

But the idea that psychoactivity is a (or the?) determining characteristic of a compound in determining whether it is prohibited is silly on its face.

What does that have to do with psychedelic psychotherapy?

Opioid medication isn't psychedelic psychotherapy, nor has it ever had strong associations with anti-establishment movements.

The major difference is that opioids had been used for pain treatment in modern medicine decades before the war on drugs, so legal prohibitions on recreational opioids didn’t affect basic research nor the development of new treatments, nor did it affect the legitimacy of opioid treatments in the eyes of the US medical establishment. (perhaps it should have!)

By contrast, psychedelics have not been used in medicine and were/are not considered “legitimate” by the medical establishment. So with legal prohibitions on actually obtaining and administering psychedelics, the War on Drugs actually did hinder psychedelics medical research.

You’re correct and parent is correct. War on Drugs started as a combined anti-black anti-counterculture initiative in response to Vietnam War. Psychedelics were threatening the power structure. It was never really about drugs.

There is also an argument to be made that Timothy Leary made a real mess of things and at minimum, certainly didn't help the situation any.

I've helped scan and archive Timothy Leary's stuff (I was dating his testamentary executor for a while). He certainly had an interesting life! I don't see how he made a mess of things.

First and foremost, thank you for your work! And I would certainly say you're likely considerably more versed than I. From my research, I felt like his escapades at Millbrook and also his shenanigans with harvard did 2 things: On Millbrook, pushed away from his work as serious work and more towards play, that rubbed people the wrong way. On Harvard, I don't think the universities were as open to ideas in that direction after he caused a ruckus. I did quite a bit of research, but it was years ago, if you wanna drop me an email I'll see if I can rustle up the things that lead me down that thought path and send them over, it was mostly from interviews of others around that time.

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